Dimethylformamide → methyl (2S)-6-(1-[1-[(tert-butoxy)carbonyl]-3-hydroxypiperidin-4-yl]-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

HRID 1051668Notes

Reaction equation

HRID 1051668 reaction equation
[CH:1]1([O:5][C:6]2[C:15]([C:16]3[CH:17]=[N:18][NH:19][CH:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:25])[N:11]3[C:21]([O:23][CH3:24])=[O:22])[CH2:4][CH2:3][CH2:2]1.CN(C)C=O.[H-].[Na+].[CH:33]12[O:39][CH:38]1[CH2:37][CH2:36][N:35]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:34]2>C(OCC)(=O)C>[C:43]([O:42][C:40]([N:35]1[CH2:36][CH2:37][CH:38]([N:19]2[CH:20]=[C:16]([C:15]3[C:6]([O:5][CH:1]4[CH2:2][CH2:3][CH2:4]4)=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]([C:21]([O:23][CH3:24])=[O:22])[C@@H:10]([CH3:25])[CH2:9][CH2:8]4)[CH:17]=[N:18]2)[CH:33]([OH:39])[CH2:34]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 21991116tert-Butyl 7-Oxa-3-azabicyclo(4.1.0)heptane-3-carboxylateHCID 118075439(S)-methyl 5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1 (2H)-carboxylate

Product 1

HCID 118086271methyl (2S)-6-(1-[1-[(tert-butoxy)carbonyl]-3-hydroxypiperidin-4-yl]-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylateYield 78.4%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

A 100-mL round-bottom flask was charged with (S)-methyl 5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (200 mg, 0.59 mmol) and N,N-dimethylformamide (10 mL). Sodium hydride (47 mg, 1.96 mmol) was added and the mixture stirred at room temperature for 30 minutes. tert-Butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (995 mg, 4.99 mmol) was added, and the resulting solution stirred overnight at 80° C. in an oil bath. After cooling to room temperature, the reaction mixture was poured into ethyl acetate (50 mL), washed with water (3×10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 10:1, dichloromethane/methanol) to afford methyl (2S)-6-(1-[1-[(tert-butoxy)carbonyl]-3-hydroxypiperidin-4-yl]-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (250 mg, 78%) as yellow oil. MS (ESI, pos. ion) m/z 541 [M+H]+.

Workup

  1. stirringthe resulting solution stirred overnight at 80° C. in an oil bath
  2. temperatureAfter cooling to room temperature
  3. washwashed with water (3×10 mL) and brine (10 mL)
  4. dry with materialdried over anhydrous sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum
  7. customThe residue was purified via column chromatography on silica gel (eluting with 10:1, dichloromethane/methanol)

Sources & evidence

ORD record
ord-c1292c020188495984d1dcc62f806ba0
Source dataset
uspto-grants-2016_07
Patent number
US09388161B2

Reaction notes

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